PROJECT SUMMARY/ABSTRACT Investigating factors that mitigate the inflammatory response to infection may have the greatest impact on clinical outcomes in bacterial keratitis. Well-designed randomized controlled trials comparing different topical antibiotics have been unable to identify any significant difference of treatment success. Activated immune cells secret cytokines and collagenases which lead to destruction of corneal tissue. Simultaneous treatment of inflammation may reduce corneal astigmatism and opacity, thus improving visual acuity outcomes. The Steroids for Corneal Ulcer Trial (SCUT) was unable to identify a benefit or harm to the use of adjuvant steroids in the treatment of bacterial ulcers overall, however, hypothesis-generating subgroup analysis consistently suggested a benefit in severe, non-Nocardia ulcers treated with early steroids. Here, we propose the Steroids and Cross-linking for Ulcer Treatment II (SCUT II), an international, randomized, double-masked, clinical trial designed to evaluate the benefit of adjuvant corneal cross-linking (CXL) and early steroids in the treatment of bacterial ulcers. Patients presenting to one of the Aravind Eye Hospitals in India or to UCSF with smear-positive typical (i.e. non-Nocardia or Mycobacteria) bacterial corneal ulcers and moderate to severe vision loss, defined as Snellen visual acuity of 20/40 or worse, will be eligible for inclusion. Those who agree to participate will be randomized to one of three treatment groups: Group 1: Standard Therapy Group, topical 0.5% moxifloxacin plus topical placebo plus sham CXL Group 2: Early Steroid Group, topical 0.5% moxifloxacin plus topical 0.05% difluprednate plus sham CXL Group 3: CXL Group, topical 0.5% moxifloxacin plus topical 0.05% difluprednate plus CXL This approach is innovative for a number of reasons including its testing of novel treatments such as topical difluprednate 0.05% and corneal cross-linking. It is also aligned with the priorities of the NEI including the study of infectious processes, as well as studying new high-resolution imaging techniques such as confocal microscopy, anterior-segment optical coherence and Pentacam Scheimflug imaging to guide treatment of corneal ulceration and as potential surrogate trial endpoints in future trials. Proctor has a proven track record of studying the optimal treatment of corneal ulceration with large NEI-funded trials. Corneal opacity remains one of the leading causing of blindness worldwide and we anticipate that this research will guide clinicians on the best management of cornea infection to reduce the morbidity associated with this condition.